3HI6

Crystal structure of intermediate affinity I domain of integrin LFA-1 with the Fab fragment of its antibody AL-57

Summary for 3HI6

• Entry DOI: 10.2210/pdb3hi6/pdb
• Related: 3HI5
• Descriptor: Integrin alpha-L, Heavy chain of Fab fragment of AL-57 against alpha L I domain, light chain of Fab fragment of AL-57 against alpha L I domain, ... (6 entities in total)
• Functional Keywords: integrin, i domain, fab, ligand mimetic antibody, cell adhesion, alternative splicing, calcium, disulfide bond, glycoprotein, magnesium, membrane, polymorphism, receptor, transmembrane, cell adhesion-immune system complex, cell adhesion/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P20701
• Total number of polymer chains: 6
• Total formula weight: 135359.17

Authors

Zhang, H.,Wang, J. (deposition date: 2009-05-19, release date: 2009-09-22, Last modification date: 2024-10-16)

Primary citation

Zhang, H.,Liu, J.H.,Yang, W.,Springer, T.,Shimaoka, M.,Wang, J.H.
Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1.
Proc.Natl.Acad.Sci.USA, 106:18345-18350, 2009

PubMed Abstract: The activity of integrin LFA-1 (alpha(L)beta(2)) to its ligand ICAM-1 is regulated through the conformational changes of its ligand-binding domain, the I domain of alpha(L) chain, from an inactive, low-affinity closed form (LA), to an intermediate-affinity form (IA), and then finally, to a high-affinity open form (HA). A ligand-mimetic human monoclonal antibody AL-57 (activated LFA-1 clone 57) was identified by phage display to specifically recognize the affinity-upregulated I domain. Here, we describe the crystal structures of the Fab fragment of AL-57 in complex with IA, as well as in its unligated form. We discuss the structural features conferring AL-57's strong selectivity for the high affinity, open conformation of the I domain. The AL-57-binding site overlaps the ICAM-1 binding site on the I domain. Furthermore, an antibody Asp mimics an ICAM Glu by forming a coordination to the metal-ion dependent adhesion site (MIDAS). The structure also reveals better shape complementarity and a more hydrophobic interacting interface in AL-57 binding than in ICAM-1 binding. The results explain AL-57's antagonistic mimicry of LFA-1's natural ligands, the ICAM molecules.

PubMed: 19805116
DOI: 10.1073/pnas.0909301106

Experimental method

X-RAY DIFFRACTION (2.3 Å)